Although cefoxitin is effective against some Enterobacterales (ESBL-PE) strains, it has not yet been tested in an intensive care unit (ICU). There needs to be more information regarding its pharmacokinetics (PK), tolerance, and effectiveness under extreme circumstances. With patients presenting with cefoxitin-susceptible ESBL-PE infection, the researchers conducted a retrospective single-center investigation in a medical intensive care unit at a university hospital. Cefoxitin PK evaluation was the major objective. Efficacy, tolerability, and the development of cephamycin resistance were secondary objectives. About 41 individuals were included in the trial, the vast majority (35 patients, 85%) of whom had ESBL-PE pneumonia. A course of cefoxitin was taken for a median, interquartile range [IQR] of 5 [4-7] days. Kidney function was a major factor in determining cefoxitin serum concentrations. With a median [IQR] daily dose of 6 [6-6] g and continuous dosing, 34 patients (83% achieved the desired blood concentration (>5 × minimum inhibitory concentration (MIC) 24 hours after cefoxitin initiation. Only in individuals with severe renal impairment and those receiving renal replacement therapy were the PK/PD target serum levels for MIC up to 4-8 mg/L achieved at the normal dosage of 6 g/24 h. In 26 cases (63%), treatment failed, with 12 patients (29%) dying, 13 patients (32%) requiring a change in antibiotic medication, and 11 patients (27%) experiencing a recurrence of infection due to the same ESBL-PE. In 7 individuals (17%), cefoxitin was responsible for serious adverse effects. And 13 patients, or 32%, were found to have developed cephamycin-resistance in the same Enterobacterales strain due to underdosing. Among patients with normal renal function, it appears that continuous administration of high doses of cefoxitin is required to reach the PK/PD target. Individualized treatment planning may benefit from renal function testing, MIC determination, and therapeutic medication monitoring. There was a 63% rate of treatment failure. While the researchers did not find any serious side effects from cefoxitin, they did find a significant frequency of cephamycin-resistance development.